Jonathan Edwards
Senior Member (Voting Rights)
Moved from the NIH thread:
Perhaps it is time to re-consider the evidence on the influence of sex and other factors in the causation of ME/CFS.
This is very long but comes in parts.
Some facts and theories.
Autoimmune diseases are more common in women.
Autoimmune diseases are mediated by errors in antibody production by B cells.
Autoimmune diseases appear at random, suggesting they start with random events in B cells - which makes sense since all new antibodies are generated through random events.
Women make antibodies for themselves and for their babies. The control of antibody production includes receptors for female sex hormones, including an effect on extra follicular B cell survival. The implication of that is not clear but it may be that in women a wider range of antibodies is made in contrast to men who focus on making very specific antibodies (in follicles). This would make sense if the mother wanted to give the baby a wide range of 'starter' antibodies to help make their own.
RA gets better in pregnancy and lupus gets worse, so depending in the initial antibody mistake the problem may be further compounded or alleviated by shifts in control from sex steroids.
T cell inflammatory diseases tend not to be 'autoimmune' in the sense of finding specific anti-self T cells. (The exception is the AIRE syndrome.) The T cells just seem to be 'too busy'.
Most are associated with MHC Class I so probably CD8 T cell related.
Most have a fairly equal sex ratio, but one, ankylosing spondylitis, is more severe in men even if possibly similar in frequency.
Tissue targeting in immune disease is different in men and women. For instance rheumatic fever affects the mitral valve in women and the aortic in men. Severity in ank spond may relate to this.
ME/CFS
ME/CFS is pretty strongly related to immune stimuli from intracellular organisms - viruses and some bigger things like Q fever. Autoimmune B cell diseases are not. T cell inflammatory diseases tend to relate to infection with intracellular bacteria. All intracellular infections tend to trigger a CD8 response but also some more innate T cells like NK and CD-1/ MAIT. ME/CFS is not linked to Class I genes. So there are reasons to think ME/CS might be triggered by an innate T cell response that is not Class I restricted.
In EBV infection the gradual recovery process over weeks is associated with a strong CD8 T cell response to EBV infected B cells but probably also more innate CD56/CD57+ NK or T cell responses.
Cells that use CD56 and CD57 also use CD16, which 'borrows' antibodies made elsewhere and uses them to guide cytotoxicity.
My thought in 2018 was that a final common pathway in ME/CFS might draw on both B cell initiated autoimmunity and T cell overenthusiastic processes. But the role of infection seems to be the same for females and males with ME so that idea is weak on that point. Maybe it is more likely that true B cell random-based autoimmunity is not relevant to ME/CFS.
However, if the starting point is a T cell response and the cells involved can borrow antibodies for effector function then the more diverse pattern of female antibody production might still make women more likely to run into severe disease. This would be a bit like the reverse of ankylosing spondylitis where the male tissue response was the main factor in disease severity.
And of course it would allow for something looking rather like ME/CFS to occur in autoimmune diseases where antibody production is generally uncontrolled - which means lupus and Sjogren's specifically. In that situation the T cell regulation may be OK but misbehaviour is driven by the presence of a blur of unhelpful antibodies being picked up by CD16.
The next bit of the puzzle is PEM and crashes. These seem to be salient if not unique in ME/CFS. Psoriasis can wax and wane with stimuli but not in the same way and most other T cell diseases don't much. Maybe exertion stimulates an outpouring of CD-1 or MAIT T cells over a period of days - that would be perfectly reasonable, as a response to muscle and other tissue use requiring increased patrolling and tissue repair. Maybe not so much an outpouring as a waking up of certain interactions in extra follicular lymph mode areas - producing sore nodes and sore throat. The hypothalamus would very likely be involved in 'counting' the exertion, just as it counts how much you eat at lunch, and sending out signals to the lymph nodes.
In this model, the female emphasis on wide spectrum antibody production would explain the sex ratio but have nothing to do with the specific random errors of autoimmunity. An overenthusiastic T cell response might occur in both sexes equally but if men have a less varied antibody spectrum there may be less chance of CD16 picking up antibody that can engage in signal production.
Nevertheless, it is still possible that antibody regulation loops quite similar to those seen in autoimmunity can contribute even if 'piggy-backed' onto T cell misbehaviour. The analogy would be the antibodies in coeliac disease, which is dependent on a continuing T cell response to gluten in diet.
If this sort of model is right then maybe the signalling pathway that needs blocking is not the 'riot police' fever signal based on TNF and IL-1 but a 'morning after clear up' signal that follows exertion and is normally unnoticed but which can have quite profound effects - as seen for instance after major surgery when nitrogen metabolism shifts and appetite changes.
Perhaps it is time to re-consider the evidence on the influence of sex and other factors in the causation of ME/CFS.
This is very long but comes in parts.
Some facts and theories.
Autoimmune diseases are more common in women.
Autoimmune diseases are mediated by errors in antibody production by B cells.
Autoimmune diseases appear at random, suggesting they start with random events in B cells - which makes sense since all new antibodies are generated through random events.
Women make antibodies for themselves and for their babies. The control of antibody production includes receptors for female sex hormones, including an effect on extra follicular B cell survival. The implication of that is not clear but it may be that in women a wider range of antibodies is made in contrast to men who focus on making very specific antibodies (in follicles). This would make sense if the mother wanted to give the baby a wide range of 'starter' antibodies to help make their own.
RA gets better in pregnancy and lupus gets worse, so depending in the initial antibody mistake the problem may be further compounded or alleviated by shifts in control from sex steroids.
T cell inflammatory diseases tend not to be 'autoimmune' in the sense of finding specific anti-self T cells. (The exception is the AIRE syndrome.) The T cells just seem to be 'too busy'.
Most are associated with MHC Class I so probably CD8 T cell related.
Most have a fairly equal sex ratio, but one, ankylosing spondylitis, is more severe in men even if possibly similar in frequency.
Tissue targeting in immune disease is different in men and women. For instance rheumatic fever affects the mitral valve in women and the aortic in men. Severity in ank spond may relate to this.
ME/CFS
ME/CFS is pretty strongly related to immune stimuli from intracellular organisms - viruses and some bigger things like Q fever. Autoimmune B cell diseases are not. T cell inflammatory diseases tend to relate to infection with intracellular bacteria. All intracellular infections tend to trigger a CD8 response but also some more innate T cells like NK and CD-1/ MAIT. ME/CFS is not linked to Class I genes. So there are reasons to think ME/CS might be triggered by an innate T cell response that is not Class I restricted.
In EBV infection the gradual recovery process over weeks is associated with a strong CD8 T cell response to EBV infected B cells but probably also more innate CD56/CD57+ NK or T cell responses.
Cells that use CD56 and CD57 also use CD16, which 'borrows' antibodies made elsewhere and uses them to guide cytotoxicity.
My thought in 2018 was that a final common pathway in ME/CFS might draw on both B cell initiated autoimmunity and T cell overenthusiastic processes. But the role of infection seems to be the same for females and males with ME so that idea is weak on that point. Maybe it is more likely that true B cell random-based autoimmunity is not relevant to ME/CFS.
However, if the starting point is a T cell response and the cells involved can borrow antibodies for effector function then the more diverse pattern of female antibody production might still make women more likely to run into severe disease. This would be a bit like the reverse of ankylosing spondylitis where the male tissue response was the main factor in disease severity.
And of course it would allow for something looking rather like ME/CFS to occur in autoimmune diseases where antibody production is generally uncontrolled - which means lupus and Sjogren's specifically. In that situation the T cell regulation may be OK but misbehaviour is driven by the presence of a blur of unhelpful antibodies being picked up by CD16.
The next bit of the puzzle is PEM and crashes. These seem to be salient if not unique in ME/CFS. Psoriasis can wax and wane with stimuli but not in the same way and most other T cell diseases don't much. Maybe exertion stimulates an outpouring of CD-1 or MAIT T cells over a period of days - that would be perfectly reasonable, as a response to muscle and other tissue use requiring increased patrolling and tissue repair. Maybe not so much an outpouring as a waking up of certain interactions in extra follicular lymph mode areas - producing sore nodes and sore throat. The hypothalamus would very likely be involved in 'counting' the exertion, just as it counts how much you eat at lunch, and sending out signals to the lymph nodes.
In this model, the female emphasis on wide spectrum antibody production would explain the sex ratio but have nothing to do with the specific random errors of autoimmunity. An overenthusiastic T cell response might occur in both sexes equally but if men have a less varied antibody spectrum there may be less chance of CD16 picking up antibody that can engage in signal production.
Nevertheless, it is still possible that antibody regulation loops quite similar to those seen in autoimmunity can contribute even if 'piggy-backed' onto T cell misbehaviour. The analogy would be the antibodies in coeliac disease, which is dependent on a continuing T cell response to gluten in diet.
If this sort of model is right then maybe the signalling pathway that needs blocking is not the 'riot police' fever signal based on TNF and IL-1 but a 'morning after clear up' signal that follows exertion and is normally unnoticed but which can have quite profound effects - as seen for instance after major surgery when nitrogen metabolism shifts and appetite changes.
